Gluten Cross-Reactivity UPDATE: How your body can still think you’re eating gluten even after giving it up.

March 13, 2013 in Categories: , , , , , by

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The Paleo Approach by Sarah BallantyneIn my research for The Paleo Approach, I feel that it is important to provide scientific references for every single statement I make.  This has me doing a great deal of fact checking, scouring the medical literature to verify information often gleaned from other paleo authors and bloggers.  Most of the time what I find out just helps reinforce concepts, filling in blanks, and typically making a strong case for my assertions.  But, every once in a while, I find information that makes me completely reevaluate a concept and sometimes even an aspect of the autoimmune protocol.

The update for this blog post comes from my further examination into the science behind gluten cross-reactivity.  While there are plenty of papers confirming how cross-reactive antibodies can be formed, I could not find any published studies confirming the results from Cyrex Labs (and my motto with the paper is if I can’t cite it, I don’t say it).  I contacted the company to request further information (I was particularly interested in the reported cross-reactivity to tapioca as I was trying to decide whether or not tapioca starch and/or pearls should be included in The Paleo Approach).  Cyrex labs responded quickly and informatively and my level of esteem for that company (which was high to begin with) elevated another couple of notches.  While they were unwilling to share proprietary data with me, they were able to point me to a recent publication that evaluated gluten cross-reactivity and share a summary of their proprietary findings (the paper did not show up on my PubMed searches).  As I devoured the paper (figuratively, not literally), I realized that an update to this post was required.  This is not an excerpt from The Paleo Approach but it is a direct result of my research for the book and much of the information that follows is still presented in it.

For those 20% of us with celiac disease or gluten-intolerance/sensitivity (whether diagnosed or not), it is critical to understand the concept of gluten cross-reactivity. Essentially, when your body creates antibodies against gluten, those same antibodies also recognize proteins in other foods. When you eat those foods, even though they don’t contain gluten, your body reacts as though they do. You can do a fantastic job of remaining completely gluten-free but still suffer all of the symptoms of gluten consumption—because your body still thinks you are eating gluten. This is a very important piece of information that I was missing until recently.

Proteins are made of long chains of amino acids (small proteins may only be 50 amino acids long whereas large proteins may be 2000 amino acids long) and it is the specific sequence of these amino acids that determines what kind of protein is formed. These amino acid chains are folded, kinked and buckled in extremely complex ways, which gives a protein its ‘structure’. This folding/structure is integral to the function of the protein.

An antibody is a Y shaped protein produced by immune cells in your body. Each tip of the Y contains the region of the antibody (called the paratope) that can bind to a specific sequence of amino acids (called the epitope) that are a part of the protein that the antibody recognizes/binds to (called the antigen). The classic analogy is that the antibody is like a lock and a 15-20 amino acid section of a protein/antigen is the key. There are 5 classes (or isotypes) of antibodies, each with distinctive functions in the body. The IgE class of antibodies are responsible for allergic reactions; for example, when someone goes into anaphylaxis after eating shellfish. The two classes IgG and IgA are critical for protecting us from invading pathogens but are also responsible for food sensitivities/intolerances. Both IgA and IgG antibodies are secreted by immune cells into the circulation, lymph, various fluids of the body (like saliva!) and tissues themselves. And both IgG and IgA antibodies are found in high concentrations in the tissues and fluids surrounding the gut (this is part of why the gut is considered our primary defense against infection).

The formation of antibodies against an antigen (whether this is an invading pathogen or a food) is an extremely complex process. When antibodies are being formed against a protein, the antibodies recognize specific (and short) sequences of amino acids in that protein. Depending on how the antigenic protein is folded, certain amino acid sequences in that protein are more likely to be the target of new antibody formation than others, simply because of the location of that sequence in the structure of the protein. Certain sequences of amino acids are more antigenic than others as well (i.e., more likely to stimulate antibody formation). This is also part of why certain foods have a higher potential to cause allergies and sensitivities.

Understanding that antibodies recognize short sequences of amino acids and not an entire protein is key to understanding the concept of cross-reactivity (and molecular mimicry, but that’s a topic for another post). It also is the reason why many different antibodies can be formed against one protein (this redundancy is important for protecting us from pathogens). Many different antibodies can also be formed against one pathogen or, more relevant to this discussion, one specific food.

So what happens in cross-reactivity? In this case the amino acid sequence that an antibody recognizes is also present in another protein from another food (in the case of molecular mimicry, that sequence is also present is a protein in the human body). There are only 20 different amino acids, so while there are millions of possible ways to link various amount of each amino acid together to form a protein, there are certain amino acid sequences that do tend to repeat in biology.

The take home message: depending on exactly what antibody or antibodies your body forms against gluten, it/they may or may not cross-react with other foods. So, not only are you sensitive to gluten, but your body now recognizes non-gluten containing foods as one and the same. Who needs to worry about this? Any of the estimated 20% of people who are gluten intolerant or have celiac disease, i.e., have formed antibodies against gluten.

A recent study evaluated the potential cross-reactivity of 24 food antigens.  These included:

  • Rye
  • Barley
  • Spelt
  • Polish Wheat
  • Oats (2 different cultivars)
  • Buckwheat
  • Sorghum
  • Millet
  • Amaranth
  • Quinoa
  • Corn
  • Rice
  • Potato
  • Hemp
  • Teff
  • Soy
  • Milk (Alpha-Casein, Beta-Casein, Casomorphin, Butyrophilin, Whey Protein and whole milk)
  • Chocolate
  • Yeast
  • Coffee (instant, latte, espresso, imported)
  • Sesame
  • Tapioca (a.k.a. cassava or yucca)
  • Eggs

They did not find cross-reactivity with all of these foods (as is implied by the Cyrex Labs gluten cross-reactivity blood test, a.k.a. Array 4).  But, they did find that their anti-gliadin antibodies (antibodies that recognize the protein fraction of gluten) did cross-react with all dairy including whole milk and isolated dairy proteins (casein, casomorphin, butyrophilin, and whey)—this may explain the high frequency of dairy sensitivities in celiac patients—oats, brewer/baker’s yeast, instant coffee (but not fresh coffee), milk chocolate (attributable to the dairy proteins in chocolate), sorghum, millet, corn, rice and potato.

While not all people with gluten sensitivities will also be sensitive to all of these foods, they should be highlighted as high risk for stimulating the immune system.   Just like trace amounts of gluten can cause a reaction in at least those with celiac disease (the threshold for a reaction has not been tested in non-celiac gluten sensitivity), even a small amount of these foods can perpetuate inflammation and immune responses. This is important when you think of the small amounts of corn used in so many foods and even the trace milk proteins that can be found in ghee.

Beyond this gluten contamination is common in the food supply and many grains and flours that are inherently gluten free may still contain gluten once processed.  Commonly contaminated grain products include millet, white rice flour, buckwheat flour, sorghum flour, and soy flour.  As these are commonly used ingredients in commercial gluten-free baked goods, extreme caution should be exercised.

Cyrex Labs offers a simple blood test that is referred to as their gluten ross-reactivity panel, a.k.a. Array 4.  It tests for reactions to the gluten cross-reactors mentioned above as well as the non cross-reactors evaluated in the paper.  Cyrex Labs reported to me that they see positive sensitivities frequently (many as high as 25%) in many of those foods in people with diagnosed gluten sensitivity.  This may reflect that when you have a leaky gut, food intolerances are quite easy to form.

If you have autoimmune disease (which has a very high correlation with gluten-sensitivity), celiac disease, gluten-sensitivity, or are simply not seeing the improvements you were hoping for by following a standard paleo diet, one or all of these foods may be the culprit. You have the choice of either cutting these foods out of your diet and seeing if you improve or get tested to see if your body produces antibodies against these foods.

When I first wrote this blog post, it made so many pieces of the puzzle come together.  I stopped eating chocolate (I had already given up coffee), fermented foods like sauerkraut and kombucha (because of the yeast content), eggs, and tapioca.  Over the months that followed, I was able to definitely discern that I am very sensitive to chocolate (perhaps because it is extremely high in phytic acid, discussed in this post) and eggs (discussed in this post).  I have successfully reintroduced fermented foods and have not been particularly inspired to test my sensitivity to tapioca (I test by eating a bit and seeing if I have a reaction, most typically my reactions are acne, but sometimes trouble sleeping, mood issues, joint aches, or increased itchiness and redness of my lichen planus lesions).  So, will I give coffee a try now?  Maybe, once in a while as a special treat, but removing gluten cross-reactivity from the list of ways coffee is suboptimal, really only removes one potential problem.  Coffee still has effects on cortisol and still correlates with increased inflammation.  Oh well.  Whether I can drink coffee again or not, I am glad to be able to share this updated information with all of you!

A great overview of proteins and antibodies (and source of protein folding image):

A fairly technical review of food IgG-mediated food sensitivities:

Cyrex Labs Array 4:

Image of antibody binding taken from

A. Vojdani and I. Tarash, “Cross-Reaction between Gliadin and Different Food and Tissue Antigens,” Food and Nutrition Sciences, Vol. 4 No. 1, 2013, pp. 20-32.

Thompson T et al. Gluten contamination of grains, seeds, and flours in the United States: a pilot study. J Am Diet Assoc. 2010 Jun;110(6):937-40. doi: 10.1016/j.jada.2010.03.014.


Thank you for this extremely interesting and informative information. I have been gluten and dairy free for about 5 years, and have such rigorous control over what I eat, that I can quickly tell what my body doesn’t like. But it has seemed so random at times, that it is hard to figure out a pattern. Yours is the first writing that I’ve seen that mentioned fermented foods as possibly problematic, so it was reassuring since I’ve sadly realized I can’t eat fermented cabbage without issues. Strangely, some chocolate is ok, other isn’t, without relation to cacao content. Some wine is ok, other wine isn’t. What I’ve read on that is that perhaps it is certain strains of yeast that one might be more sensitive to over others. But I am now very interested in taking this test; perhaps it will help with some of the mysterys.

Thanks for the excellent article. Regarding the Cyrex slabs study, I notice that while they tested “Coffee (instant, latte, espresso, imported)” per the bullet points, in the ensuing paragraph you note that they only found the anti-gliadin antibodies’ cross reaction to “instant coffee (but not fresh coffee).” Is the culprit the fresh coffee or the “junk” that ends up in the processed instant coffee? Thanks again for the great material!

Hi, i got my rsults back and am out of range for eggs and several other things. My question about eggs is whether that is to both the whites and the yolks? I left this question for them but havent heard back.

This just in from Cyrex Labs concerning whether their test is for egg yolks or egg whites – they test both so if its a positive result (out of range) then it is for the whole egg. Darn!

My doctor/researcher husband was appalled that they report “high negative” results as low positive or equivocal. He insisted that a negative result is a negative result and that it is bad science to report otherwise. Is allergy testing different? I don’t want to eliminate foods I don’t have to. I guess observing symptoms is the only sure way to know.

Hi Sarah,
Thanks for all your great work!

I started seeing a holistic nutritionist about a year ago. At that time I had been gluten free for about 1 1/2 years (celiac). I was feeling totally fine, but just wanted to make sure I was getting all of the right nutrients, pairing foods together correctly etc. She recommended I do a leaky gut protocol and take the Array 4 test. Lost of foods came back on it, I cut them out for 6 months and reintroduced and then retested. The only food I felt any reaction to was rice (a little bloated). The foods that came back were , most grains (corn, buckwheat and quinoa were fine), whey was equivocal, yeast, and tapioca.

My question is, if I had gone into this and decided to cut those foods out and reintroduce without taking the Cyrex test, I would have thought all of them were ok (except rice) because I had no noticeable reaction. Mood stayed fine, gut reactions, headaches, general inflammation, etc. I didn’t notice anything. I had them back in my system for approx 2 months before retesting. I have omitted all of them after the retesting since mid-December.

I saw a new holistic doctor for a 2nd opinion and he said that those tests were a good start, but that its possible my gut wasn’t really totally healed yet, and that if I healed it all the way, he didn’t see a reason I couldn’t eventually add those foods back in. For my purposes if that were the case, I would do it on a limited and rotational basis, but it sure would be nice to not have to scrutinize everything, and be able to travel internationally again!

Also, speaking of international travel. If I were to travel and ate some of these foods for a week or 2 weeks, and was asymptomatic, would it be ok? But was strict for the rest of the year?

Thanks for all of your help!

I agree with the 2nd holistic doctor. As for traveling, it depends on here you are in your healing when you do it, what you eat, how nutrient-dense your diet is, how well your stress is managed, how well you sleep… but, in principle, yes, you might be able to do that.

Hi Sarah, ive found all the info on your blog really helpful. One of my friends has had a lot of success with resistant starch, and suggested I try it. However, potato is out on AIP. I live in the uk and i havent been able to find anyond selling plantain chips or flour over here. I was thinking of trying tapioca starch, but I was a bit confused as to whether it is allowed or not. Thanks Rachel

I thought I knew nearly everything about gluten-free and paleo….but this Xmas when I made a rice pie crust (I only indulge in rice 2x a year) with tapioca instead of arrowroot, I was unprepared for the searing joint pain. I did not know it was a nightshade!(I do not eat tomatoes or white potatoes.) I woke up screaming in pain and just now, one-and-a-half months later, am recovering from pain, brain fog, bloat, constipation, etc…. It has been excruciating.

Sarah – I love all of your articles and have learned so much. After suffering from almost nightly painful gas, I switched in January to a Paleo diet and probiotic pills and have seen definite improvement. I have occasional relapses with gas when I try new foods that should be Paleo that lead me to question exactly what my issue is – lactose intolerant, celiac disease, gluten sensitive or what. Is there any easy way to get tested for all of this including cross reactivity without all the trial and error? Thanks for your help.

I am not saying that they are not cross reactive – but cassava and tapioca and yams are not nightshades. They are in a different botanical family. I was surprised when I read that here. Why do you believe that they are nightshades?

Thanks for such an informative post. I’ve been on an autoimmune protocol with my naturopath for 3 years now to treat leaky gut and many other symptoms derived from it. It’s been helpful getting testing on every ingredient before I add it to my diet, it’s slow but gradually moving. But one thing I want to add is obviously dysbiosis is a big issue with leaky gut and treating the parasite makes a big difference. It’s been a reoccurring issue for me but one that needs to be addressed if you want the condition to improve.

Thanks Sarah for all your work, you’re my idol!! :)

Are duck eggs and goat milk inc. in this “dairy”
Thank you for some great info my 11 yr old has Crohns and the ELISA test was wonderful. Is there a difference in the test?

Thanks for this informative article. I’ve known about cross reaction for several years, just not the science. This will make it easier to explain to people why I can’t eat any grains etc. I also suspected I should give up chocolate, but have been able to talk myself out of it until now.

Sarah, thank you for this post! We are trying to follow the GAPS diet for our son, 19 mo. He was muscle tested for sauerkraut a few months back and was weak to it. It’s so high priority in GAPS and it’s really bugged me that he tested weak to it, as I don’t want to impede his healing in any way. He has also thrown up after ingestion of quinoa (even soaked and sprouted) – we were trying to incorporate some gluten-free carbs to cut back on our budget. Again, this article explains why this could happen.

You’ve been at this longer than I have – have you heard of Paleo people being able to incorporate properly prepared grains in their diet after a few years of healing? Thanks, Sarah!

Just wondering if you could please confirm when you mention ‘potato’ on the cross-reactivity list, is this just white potato? Also, when you mention ‘tapioca’ would this include sweet potato as well? I get a little confused between the two as I’ve only seen tapioca in the pearl or starch form… not as a root vegetable.

One last thing, do you know of any reputable testing laboratories in Brisbane, Australia? I have been on the food elimination/trial-and-error for way too many years and wondering if I do the blood testing would it confirm foods that would definitely react with me? Thank you!

This was the case for me and pregnancy! My body was attacking ‘pregnancy tissue’ thinking it was gluten due to similar protein sequence. Very interesting! Having miscarriage or fertility issues, consider gluten being the issue.

I started seeing a Functional Medicine Practitioner around the same time I bought your book – I am slowly reading through it, trying to absorb all of the fantastic science. My Dr. ordered the Cyrex Array 4, and while I was doing more research on it, I stumbled across this article. I am so grateful for all of your hard work, and your commitment to accurate information. I’m looking forward to seeing my results, because I have not noticed a big difference simply cutting out gluten. I have Hashimotos Thyroiditis, and I’m very hopeful that following the Paleo Approach will help alleviate some of my symptoms.

Hello Sarah,
If a person does not have a gluten problem, but is going to adopt this life style due to another autoimmune disorder, Hashimoto for example, is it true that once you go gluten free you can never eat gluten again? And if that is true, can this same person end up with Gluten Cross-Reactivity too? I have ordered your book, thank you for writing it.

Absolutely amazing info here. I can’t tell you how thankful I am to have this all in one place! I have been struggling with understanding the tests I took with Cyrex labs (Cross Reactive Foods and Gluten Sensitivity), and this helps. I found out I have a gluten sensitivity in transgutaminase 3 IgG (mainly effecting the epidermis) and I am still trying to fully understand what that means. While my doc did explain this a bit, there is much I do not understand! I do wish there was info all in one place for that also!!

I’ve been searching for an answer to my question by reading your site and the general internet for a while now but I’ve not been able to find a specific answer. I used to get frequent migraines which have stopped after cutting out gluten. I seem to be more sensitive to it now and get occasional migraines after contamination, however I don’t have GI symptoms, just “low normal” ferritin/B12 levels and hair loss. Does this mean I must have leaky gut or do some people have purely neurological symptoms from the gluten and the hair loss is unrelated? I’ve been trying to do the “right thing” for gut healing by avoiding dairy and rice, taking probiotics, L-glutamine and vitamin supplements but my hair doesn’t seem to grow back as much as I want it to, and I don’t want to bombard my body with supplements if I don’t need to.. I wish I could ask my doctor, but he didn’t even believe me when I told him that gluten was the culprit for my migraines! Any insight would be much appreciated!

Thanks Christina for your reply! I had never even heard of leaky brain (new to this gluten thing) so now I have even more stuff to worry about ha ha!

Have you looked into a sensitivity to free glutamates? A lot of people suffer headaches from it, and experience relief when cutting out gluten and dairy, because they are lightening their protein load. Also, most doctors know very little when it comes to food issues, I’ve found. Good luck!

I have multiple food allergies, the IgE kind, to gluten, wheat, barley, rye, eggs, and a number of other foods. I have diagnosed Eosinophilic Esophagitis via biopsy and I’ve been scoped and blood tested (IgA and IgG) for Celiac disease which came up negative. I suspect I have leaky gut (based on symptoms of depression, lack of energy, etc.) which co-exists with my food allergies. The trouble is I cannot find any material linking IgE mediated allergies to leaky gut. The material I find always discusses IgA and IgG mediated reactions and leaky gut.

Can IgE mediated food allergies also cause leaky gut?

Thank you for your response!

I’ve been trying to clean up my diet for over a year now. It’s a yo-yo. The harder I try, the harder I fall. Binging on carbs and sugary foods when i fall has me extremely frustrated. I know there will be immediate allergic reactions and long-term after effects but the cravings are simply overpowering. And its been getting worse lately.

The whole paleo diet is a bit overwhelming. It’s tough to completely change my processed diet. I’m trying to change my diet slowly, eating more veggies, healthy protiens, healthy fats, and fewer sweets and diet soda. Eventually I hope to have a large enough list of allergy free, healthy food options so I don’t feel too restricted and end up falling back to the same old garbage.

I’m focusing on leafy greens, and other veggies I like. I’m also working my way toward healthy, protien packed meats like fish, turkey, and chicken along with allergy-free carbs like white rice. Of course, I’m also trying to avoid sugar and the foods I’m allergic to. I plan to include pro-biotic and glutamine supplements too, but want to keep it simple.

Are there any other ‘keep-it-simple’, big-ticket items you’d recommend?

I am a celiac, gluten-free for a year and a half. I also have RA and other conditions that have been related to CD. Recently, after 3 rounds of severe abdominal pain (which I never had prior to the CD diagnosis), I have now been diagnosed with an “aggravated” gall bladder with gall stones and my doctor wants to remove my gall bladder. Could this have been caused by celiac disease? Can a paleo diet help reverse this? If not, can a paleo diet help one adjust to the side effects of not having a gall bladder?

I am following the AIP diet. If I did the Array 4 and find that I am not reacting to rice (or any other grain), does that make it a safe food or while following AIP do all grains need to be removed regardless of a sensitivity?

No. The best way to determine sensitivity is to remove foods and then reintroduce them. Also, the Array 4 may not pick up sensitivities to any foods you have already been avoiding. – Christina, Sarah’s assistant

This article changed my life. I read it a while ago before I knew for sure that I was celiac and cut out almost all of the cross reactive foods mentioned. Now, since I got dermatitis herpetafomis (gluten rash) for the first time I KNOW I am celiac and I am being even more careful than ever. Baby steps! I hope to get Cyrex Labs testing done for Array 4 if I can figure out a doctor who has an account (I am in NY and looking to go to VT since Cyrex is not allowed to test here). Thank you so much for all that you do sharing this valuable info with everyone!!

Hello! I understand the milk issue in chocolate, but what about dark chocolate & cocao powder? Should these be avoided? Thanks for your time!

My daughters and I had Cyrex Array 4 performed. Our doctor said we should never add back Rye,barley spelt,polish wheat, Cow’s milk, oats, yeast, millet and corn. We diligently avoided all problem foods for a year and have successfully healed leaky gut. Of the list of
24 items on array, why do we have to avoid oats, yeast, millet and corn? Are these just considered more problematic for some reason, or should we just see how each of our bodies responds to each allergy? Should we avoid kombucha because of the yeast, and should all yeast be avoided? Lastly, my hair is thinning and falling out despite so many positive lifestyle changes over the year. So many things are moving in the right direction but the hair is a problem? Any thoughts?

Well, there are lots of ways that grains can be a problem that won’t show up on tests, but there’s still individual variation in responses. However, I think that if your hair is falling out (could be hypothyroid or alopecia, both things you should talk to a doctor about), that’s probably a sign that your gut has not yet healed.

I, too, have had the Array 4 done and am now, in addition to wheat, avoiding milk protein, and soy (all positive). I feel SO much better in every way, but am also experiencing increased hair shedding and am extremely frustrated. I was taking an iron supplement after my last doctor told me I had low iron, then stopped iron as my new doctor (who did the Array 4) told me my iron was high (Ferritin 40; Serum Iron 187 which was the high one). So I stopped taking iron supplements and started the Gut Repair Diet, at which time my hair loss and shedding increased dramatically, so it’s hard to know if it was the diet, or stopping taking iron which has contributed. I will start iron again after seeing this post, thank you!. It looks like an optimum range is 60 for ferritin anyhow, so I had a little ways to go even before I stopped taking it.

Thank you for this information. I took array 4 last December and also discovered I had a strong reaction to eggs. Also some reaction to oats, soy and coffee which i didnt use anyway.
It has been easy to eliminate eggs. I had the question about yolks and whites and saw it answered above.
However, were these tests done on pastured eggs? grain free chickens that is?
is the only way to test for sensitivity to duck or goose egss (to which I have access) , at this time, by eating and awaiting symptoms?
For the strong reaction to eggs shown on cyrex, I felt almost nothing in my body. I have determined now that it was causing a ‘hot brain’ feeling that came periodically but not directly correlating to the timing of eating the eggs. Being on WAPF and having done GAPS, I had been eating 2+ eggs daily for about 3 years. I am horrified to imagine what I had been doing to my blood brain barrier.
Looking forward to getting and using your book very soon.
Thank you!

I’m not sure what type of eggs were used. It’s true that many people who do not tolerate conventional eggs do well with pastured eggs. The best way to determine sensitivity to any food is to eat it and see how you do. – Christina, Sarah’s assistant

I don’t think that this makes sense. Pastured eggs, conventional eggs, duck eggs all have the same kind of protein. Isn’t the test looking for sensitivity to the protein?

Eggs have been shown to contain the protein of foods the hens were fed (like soy), so those with soy sensitivity may not be able to tolerate soy-fed eggs. In that case, a person who does not tolerate conventional eggs may tolerate pastured eggs because the sensitivity has nothing to do with the actual egg proteins. – Christina, Sarah’s assistant

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